L17 Toxicology Flashcards
What are the two main aspects of toxicology
Basic science and risk assessment
What is the principle of toxicology
The dose makes the poison
What are some common toxicants
Natural toxins (produced by living systems for self defence)
- Mycotoxins (fungi)
- Phytotoxins (plants)
- Animal toxins
Synthetic toxicants
- industrial chemicals, plastics
What do galanthamines do?
Inhibit acetylcholinesterase (enzyme that breaks down acetylcholine in synapses)
Competitive inhibitor
*Organophosphates are also competitive inhibitors
unlike organophosphates, they bind reversibly to the enzyme
What do cardiac glycosides (e.g. digitalis) do?
Inhibit Na/K pump, cardiac mycocytes gain Ca which increases contractility and increases risk of arrhythmia
TF: cardiac glycosides can be used to treat heart failures and irregular heartbeats
True
What does ricin do?
Blocks protein synthesis
B chain binds to cells while A chain inhibits ribosomes
What are the main targets of animal toxins
Nervous or cardiovascular system
What is hormesis
Hormesis is the change in effect of a drug when moving from low to moderate doses of the drug
What can toxicants move through
Water, air, soil
Which drug causes the most human poisoning in North America
Analgesics (children are most vulnerable)
TF: polluted air and water are major causes of deaths from toxicants
True
Explain how polluted air can lead to toxicity in the body
Inhaled particles reach the alveoli where they are absorbed into the blood, then they reach the brain via the olfactory bulb
Explain how toxicants can affect microbiome
Swallowed pollutants can be absorbed from the GIT, thus altering microbiome
What are the 3 entry routes to the brain for toxicants
- Olfactory bulb
- Alveoli-blood
- GI-direct/microbiome
Order the following 3 in terms of which has the most toxic particles
Upper airways
Deep lung
Alveoli
Least to most: alveoli < deep lung < upper airways
TF: bioavailability does not vary with location
False
Name one way biomagnification can occur
Through the food chain
What are 6 measurements for toxicology
LD50, TD50, threshold, NOAEL, LOAEL, hormesis
*NOAEL=No observed adverse effect level
LOAEL=lowest observed adverse effect level
What is LD50, TD50, ED50, therapeutic window and therapeutic index
LD50 = dose that kills 50% of population
TD50 = dose that causes 50% of the population to be sick
ED50 = dose that causes therapeutic effect in 50% of the population
Therapeutic window is the dose range of a drug that provides safe and effective therapy with minimal adverse effects.
Therapeutic index quantifies the relative safety of drug i.e. distance between toxic/lethal dose and the therapeutic dose (LD50/ED50 or TD50/ED50)
What is NOAEL and LOAEL
NOAEL: highest data point (dose) at which there was not an observed toxic or adverse effect - No Observed Adverse Effect Level
LOAEL: lowest data point (dose) at which there was an observed toxic or adverse effect - Lowest Observed Adverse Effect Level
What is threshold?
Threshold dose is the minimum dose of drug that triggers minimal detectable biological effect in an animal
What is epidemiology
Studies that are conducted in humans to understand toxicants in different areas of the world
What are cohort studies (observational study) and the two methods used for monitoring?
A cohort of people who share certain characteristics are studied to compare disease occurrence - exposed and non-exposed groups
- prospective study: two groups are monitored for some time, it is accurate but expensive
- retrospective study: two groups are looked at at one point in time in the past to see which one has a disease, it is less accurate but faster
What is a case control study (observational study)
Compare people who have a certain disease with those who do not, always retrospective
TF: case control studies are always prospective studies
False, they are always retrospective
What are cross sectional studies
Cross-sectional studies are similar to cohort studies, but they only collect data from one point in time or over a short period. They can identify potential risks or causes for disease, but they are unable to examine whether something causes disease over a longer period.
e.g. population census
Goal: correlate different health problems with all the data collected
What are odds ratio and standard mortality ratio
odds ratio: risk of disease in exposed group vs non-exposed group
e.g. if OR = 2, the exposed group is twice as likely to develop the disease
SMR: relative risk of death based on comparison of an exposed and non-exposed group
e.g. SMR = 120, the exposed group has a 20% greater risk of death compared to the non-exposed group
What is relative risk
RR: relative risk of disease comparing exposed and non-exposed group
e.g. RR = 175, exposed group has 75% increased risk to contract disease
similar to OR or SMR
What is the difference between risk assessment vs risk management
Both are used to characterize risk, but
risk assessment = dose-response assessment, hazard identification, exposure assessment
risk management = control decision, determination of the acceptable risk level, control alternative
What are some subcategories for toxicology
forensics, ecotoxicology, specialization in species, organ systems, herbicides, etc.
What does toxicology study
it studies the adverse response in biological systems caused by chemical or physical agents
Who said “The dose makes the poison”?
Paracelsus
TF: We can characterize something as toxicant without knowing the dose-response curve
False we must know what the curve looks like
TF: Most of plant life is toxic
True
What kinds of toxins do fungi produce: phytotoxins or mycotoxins?
mycotoxins
What kinds of toxins do plants produce?
phytotoxins
Why can digitalis/foxglove plant be used as medicine?
at small doses it is effective in treating cardiac problems as it contains cardiac glycosides
TF: Toxins can act as agonists or antagonists on receptors (e.g. nicotinic receptors)
True
TF: Daffodils are poisonous
True
Explain how daffodils are toxic
Galantamine is found in daffodil bulbs, it is a competitive inhibitor of acetylcholinervse (which breaks down ACh in synapse). This causes the synapses to flood with ACh, which can paralyze you since the nAChR are always bound causing constant depolarization of the muscle - open blocked receptors
Calcium oxalate crystals are found in the stems, which can cause irritation
How are lilies of the valley toxic?
they contain glycerine poison, as well as at least 20 poisonous glycosides, which affect the cardiovascular system. These glycosides can cause cardiac arrhythmia and stop the pumping action of the heart
Name some examples of plants that contain glycosides
lily of the valley
oleander
How did cardiac glycosides get their name
they have a glycone (sugar portion)
Why are oleanders toxic?
they contain high concentrations of cardiac glycosides (inhibit Na-K pump, increase Ca inside cell, increases contractility and arrhythmia)
In what can we find ricin?
castor oil beans
Describe the structure of ricin
2 components: A and B (functional group/moiety) linked by disulphide bond (thus held tgt by disulphide bridge)
Part B allows Part A to enter the cells and disrupt protein synthesis
TF: An adult will be dead a few minutes after consuming a castor oil bean
True, the beans are very potent meaning the Letha dose is ~1mg for an adult
TF: There are no harmful compounds found in foods such as apples, pears, potatoes, and courgettes
False, they contain small amounts of harmful substancces
What poison do apple seeds contain
amygdalin
TF: mycotoxins and phytotoxins can cause cancer
True
What is the term used to refer to animal toxins
zootoxins
TF: computers contain a variety of toxic substances
True, though they are usually released when discarded
Why is it important to bring old electronics to indicated collection sites?
toxins from old electronics can leak into soil and water, which can spread. Some toxins get into the air and are deposited elsewhere
Why does poisoning mostly occur in children
Up until the age of 5, children are most vulnerable as they are unaware of the thins they are consuming
Other then during childhood, what other stage of life is vulnerable to deaths by poisoning?
Adolescence and adulthood (they are experimenting with drugs)
TF: large amounts of salt, saturated fats, and additives can be viewed as toxins
True, and it can be worse than the toxins found on the surface of the food you buy
Why is it important to consider acute and chronic toxicity?
Some substances do not have adverse acute effects, but my cause serious problems in the long term (e.g. alcohol)
Why is it more difficult to assess long-term toxic effects?
It is more difficult to link chronic toxicity to low exposure over a long time (e.g. arsenic)
TF: Although toxins can affect male and female fertility, they do not affect the fetus
False, the fetus is also affected
What are the 3 major ways we’re exposed to pollution?
air, water, soil
(soil contaminants can get into air and water)
What do pollutants mainly affect?
CV and nervous system
+GI tract which is sensitive
What is enteritis
inflammation of the small intestine
TF: In developed countries, it is more common to be harmed by pollutants in water than in air
False, air pollutants are usually more harmful than water pollutants (in developed countries)
What are some current toxicant exposure problems? (5)
tobacco smoking, secondhand smoking, air pollution, ambient particulate matter, coal burning
TF: There are more deaths associated with acute poisoning than with chronic toxicity
False, chronic toxicity is linked to more deaths
Fine particles found in gases and in the air can damager what? How?
heart, lungs, brains (affect all major organ systems)
the smaller particles that are not trapped by mucus go down into the distal airways (where they are phagocytose by alveolar macrophages)
however, ultra-fine particles can diffuse right through the alveoli and into the capillaries (where it is transported to the rest of the body like the brain)
TF: There is no evidence demonstrating impaired development in children living in highly polluted areas
False, there is. Though there is no evidence linking dementia to pollution
What are some routes of entry into the brain for fine particles
nasal-sinus region in the olfactory bulb
lungs and blood
swallowing air -> GIT (+microbiome) and blood
What is an important concept for environmental toxicology?
The environment in which the toxicant is present affects how much of it can be absorbed
e.g. pH and flow rate of water affects how much of the toxicant is available ti be absorbed - collective group of toxicants (air, water, soil) must also be considered
How can the bioavailability of a toxin vary with location?
build up of sediment can affect the food chain (from filter feeders to apex predators) i.e. biomagnification - concentration can can get up to 10 million times its initial concentration in water
Biomagnification has caused the endangerment of what species (specific example)
Canadian loon
Which is the deadliest form of food poisoning and why?
Botulinum toxin (LD50 = 0.0001 mg/kg)
TF: Botulinum toxin can be found in canned food and is used for botox
True
TF: The smaller the LD/ED ratio, the safer the drug
False, a larger difference would indicate a safer drug
What are 4 examples of toxicants that don’t have beneficial roles in humans and can be lethal in very small doses?
botulinum toxin (bacteria)
strychnine sulfate (pesticide)
rattlesnake venom
nicotine
TF: Ethanol is considered safe due to it’s large therapeutic index
False, ethanol’s LD50 and ED50 are actually quite close to each other
Which is better to consider when administering a drug, TD50 or LD50?
TD50 because we want to avoid troublesome side effects
TF: most toxins can have therapeutic effects
False, both TD50 and LD50 are considered
Why are dose response curves important when considering toxicants even if they do not show potential for therapeutic effects?
To find out their toxic threshold (dose at which toxic effects appear) or if any dose is toxic
Doing so allows us to decide whether government action must be taken to determine permissible dose of that toxicant
TF: nicotine taken in low doses does not pose any toxic effects?
False, nicotine does not have a safe dose
Although acutely there are no effects, chronic use shows dangerous adverse effects
TF: Drugs above the safer threshold are considered safe
False, drugs under the threshold are considered safe
Generally False, but digitalis for example would be true
TF: Carcinogens possess a safety threshold
False, they do not
TF: Anything in between NOAEL and LOAEL is considered safe
False, anything in between is unknown and require further study
anything under NOAEL is safe
anything under LOAEL is safe
*NOAEL = No observed adverse effect level
*LOAL = Lowest observed adverse effect level
TF: LOAEL is considered to be the safety threshold
False, NOAEL and LOAEL both consists of different thresholds used to determine the safety threshold
TF: It is possible to overdose on vitamins
True, vitamins can be harmful at high concentrations (hormesis)
Is it possible for small amounts of an otherwise beneficial substance to cause harmful effects/be toxic
Yes, small doses of antimicrobial drugs can cause AMR and increase bacterial growth rate
High doses simply eliminate the bacteria
Is the following a display of hormesis: Prostate cells in tissue culture secrete androgens at the same levels despite changes in pesticide concentration
No, as there is no change in effect (androgen release) due to change in doses of pesticide
This statement is also false, since at higher levels of pesticide, prostate cells release lower levels of androgens
TF: Animals used for research and educational purposes comprise the largest proportion of animals killed per year
False
TF: There are strict regulation for animal treatment in research and normal products
False, there are no regulations against animal cruelty in products sold
Why is warfarin used to kill rats? How does it work
It is a relatively painless death compared to glue traps. It causes internal bleeding as it is an anticoagulant
TF: cohort studies are exposure->outcome, case control studies are outcome->exposure, and cross-sectional studies are outcome->exposure
False for cross-sectional studies, which relate exposure and outcome at the same time
What is the difference between bias and confounding
Bias = non-representative/misclassification due to preconceived ideas
Confounding = factors that researched didn’t control for e.g. smoking in participants is not controlled for
TF: Conducting a prospective study minimizes the risk of confounding compared to retrospective studies
True, retrospective studies cannot control confounding factors as easily since there is not regular monitoring over time
Governments make decisions on which substances to ban based on what kinds of studies?
epidemiological studies
What group of people is most vulnerable to lead contamination and why?
children since there are more susceptible to lower doses and they put things in their mouths
though adults are also affected
What are the main targets for lead contamination
CV system, nervous system + sensitivity in kidneys, GIT
Lead contamination can be considered _ _ in children because it leads to impairment of _ _, _, _
developmental toxicity
impairment of intellectual development, hearing, and growth
TF: Lead contamination does not affect fetuses
False, it can cross the placenta and thus affect the fetus
TF: Lead is biodegradable
False
Why do pipes in older homes need to be checked?
Paint used in 1950s used to contain lead which could have contained/accumulated in water pipes
What are symptoms of lead poisoning?
short-term: psychological and mental changes, GI issues, fatigue irritability, CNS/neurological effects, joint/ankle/wrist effects
Why is lead contamination so dangerous in children
Lower doses can cause brain, hearing, nerve damage, impaired intellectual functions, digestive issues and stunted growth
Lead used to be found where?
gasoline, paint, plumbing
Why where children who lived near highways more susceptible to having lower IQs?
Lead found in gasoline affected brain development
What are the pharmacodynamic effects of lead?
Lead alters the function of calcium and zinc (divalent cations), thus affecting ion channels (neurotransmitter release) and many proteins
calcium signalling is blocked, NMDARs are blocked, mGLURs are affected, mitochondria and gene transcription are affected
End result: CNS is heavily affected
NMDAR are ligand-gated ion channels while mGLUR are g-protein coupled receptors. NMDAR are highly reliant on calcium
TF: lead inhibits ion channels only
False, lead can stimulate or inhibit ion channels depending on location and circumstances
What are some specific consequences on the CNS for children affected by lead poisoning?
smaller prefrontal cortex
impaired synaptogenesis
apoptosis of neurons
hyperexcitability
Why is are the pharmacokinetics of lead so complex?
it can be taken up from the soil, air, water, paint, dust - absorbed by the lungs and GIT
Lead gets stored in the bones, which can then later be mobilized
Where can mercury be found?
volcanoes, pollution from industries (anthropogenic) where it moves to soil, water, air
mercury becomes more toxic in soil and water is it becomes methyl mercury
Why does methyl mercury bioaccumulate?
it is not biodegradable
What are short term effects and long term effects of mercury poisoning?
short: memory loss, impaired hearing, vision, speech, tremors, lack of coordination, skin issues, difficulty chewing and swallowing
long: weakness, fatigue, anorexia, weight loss, disturbed GIT function, deteriorated nervous system
What is the Grasshopper effect
When seasons change, air masses that rose from hotter regions of the planet move north and deposit their contaminants as the air cools down
This repeats with every season change, contaminants move further North
Once up North, bioaccumulation occurs and there is magnification of mercury in Northern wildlife
What are 3 kinds of pesticides
insecticides, herbicides, pesticides
What mechanisms of action can pesticides use?
inhibit cell division, protein synthesis
herbicides aren’t super toxic but they can cause irritation
carotenoid synthesis/photosynthesis may be affected but are not targets
Why has the use of insecticides been so beneficial in the realm of human disease?
By eliminating ticks, lice, and fleas, there is less disease transmission (e.g. malaria, yellow fever, plague, etc.)
Over 30 human diseases have been decreased
What constitutes an ideal pesticide? (4)
- minimal/very low toxicity
- auto degraded/little persistence in environment
- little risk to non-target organisms (specific)
- Does not confer resistance
TF: pesticides harm different species in an equivalent manner
False
e.g. trout are resistant to parathion, but not rats
How can the use of pesticides in crops spread?
the runoff from fields gets into streams, groundwater, rivers, and the ocean
Why are lipophilic chemicals dangerous
they accumulate in body fat
TF: Pesticides are overall very toxic to humans
False, although some can be absorbed through the skin, most are not super toxic
What is the half-life for DDT (organochlorine/insecticide)
10 years
Why was DDT so useful during WW1?
It warded many insects that transmit various disease such as lice and mosquitoes
Why did people stop using DDT?
The constant use of DDT caused bioaccumulation, which made bird eggshells more fragile. This resulted in a decrease in bird population (“A Silent Spring” book was a turning point)
What is the mechanism of action of organochlorines
They act on voltage gated sodium channels
Why are insects so vulnerable to organochlorines?
Insects were sensitive to the action on voltage gated sodium channels, causing hyperexcitability (channels are open for longer) which lead to death
What is Lindane and how does it work
An pesticide/insecticide that works by blocking inhibition in bugs like termite (GABA receptors) which lead to convulsions in insects
What are Pyrethroids and how do they work? Which insects would they act on
They are insecticides derived from plants that act on voltage gated sodium channels, thus increasing hyperexcitability leading to death
lice, ticks, fleas
Name 3 kinds of insecticides
Organochlorines (act on VGSC voltage-gated sodium channel)
Pyrethroids (“)
Organophosphates (ACh breakdown inhibitor)
What is the mechanism of action of organophosphates?
they irreversibly inhibit acetylcholinesterase which is responsible for breaking down ACh
Death is due to respiratory failure
What is Malathion and how does it work
It is a manmade organophosphate that is least toxic to animals (enzyme that can metabolize it)
It causes death by excess stimulation of nicotinic receptors by ACh
Which one is an organochlorine? and organophosphate?
Lindane
Malathion
lindane = organochlorine
malathion = organophosphate
